The present invention is directed to a process for producing 1,3-dihydro-4-pyridoyl-2H-imidazol-2-ones of Formula I ##STR1## wherein R.sub.1 is a hydrogen or a 1 to 4 carbon atom alkyl group and Ar is a 2-, 3- or 4-pyridyl group as well as the pharmaceutically acceptable salts thereof. These compounds and in particular 4-ethyl-1,3-dihydro-5-(4-pyridoyl)-2H-imidazol-2-one possess potent cardiotonic utility and are useful therapeutic agents in the treatment of cardiac failure.
These compounds have been prepared in the prior art by several methods. In one method an imidazol-2-one is reacted with a pyridoyl chloride or bromide or pyridine carboxylic acid or carboxylic acid anydride in the presence of a Lewis acid catalyst, typically aluminum chloride. This process suffers from several serious drawbacks upon scale-up including extreme difficulty in mixing the solid aluminum complexes and resultant poor yields primarily due to difficulty in separating product from the solid mass of the reaction pot.
In another prior art reaction illustrated in Scheme I, a diketo-oxime of structure II is reduced to form an aminodiketone of structure III which upon reaction with a cyanate salt yields the structure I compounds. ##STR2##
Several difficulties are encountered when this process is employed. In particular, because the keto function adjacent to the pyridine ring in the structure II compounds is activated towards hydrogenation, this keto group is reduced along with the oxime group to yield to hydroxyaminoketones of formula IV. ##STR3## This side reaction necessitates removal of the structure IV compounds from the hydrogenated reaction mixture and results in lowered overall yields of the desired structure I compounds.
Applicants have discovered that improved yields of the desired product of structure I can be obtained following the reaction path of Scheme III. ##STR4##
This improved reaction scheme eliminates the need to remove any of the hydroxyaminoketone of formula IV which forms by undesired side reaction in the scheme II process. Moreover, the reaction of the hydroxyaminoketone of formula IV with cyanate ion in scheme III proceeds with substantially greater yields of cyclized product than does the corresponding reaction of the diketoamino compound of structure III with cyanate ion in the scheme II process. Applicants have found, surprisingly, that the overall conversion of structure II compound to the desired pyridoylimidazol-2-one of structure I proceeds with substantially greater overall yields when the process of scheme III is utilized rather than that of scheme II. This occurs even though the scheme III process requires an additional step which has no counterpart in the closely related prior art process of scheme II, that is, scheme III requires the oxidation of the structure V alcohol to produce the desired pyridoylimidazol-2-one.